OVERALL PROJECT SUMMARY Influenza viruses continue to pose a significant threat to global public health. Consequently, there is a vitally important need to generate new influenza virus vaccines and innovative vaccination strategies. The development of a long-lived broadly-protective influenza virus vaccine would have a tremendous impact on worldwide efforts to control influenza viruses. The purpose of this renewal is to continue on our efforts to address this need. Since the initial funding of this Program we have made major advances in our knowledge of the human immune response to influenza viruses and in our understanding of a unique class of broadly- neutralizing antibodies. We discovered new mechanisms for virus neutralization in vivo by antibodies that recognize conserved regions of the hemagglutinin glycoprotein, made new discoveries regarding B-cell induction and persistence of humoral immunity in humans, and crucially, generated novel vaccine immunogens and immunization regimens. Through this work, we have elucidated new paradigms in influenza vaccination that we plan to advance further by continuing our long established research collaboration. To achieve this, we will improve the ability of our hemagglutinin immunogens to induce antibodies with optimal effector functions. We will examine the induction and maintenance of long-lived plasma cells and use this information to identify potent B-cell adjuvants that promote long-lasting immune responses. Moreover, we will look to explore the viral neuraminidase as a target of broadly neutralizing antibodies; this surface glycoprotein has the potential to improve the overall breadth and immunogenicity of a universal vaccine. This approach will be combined with parallel efforts to generate universal stalk-based vaccines for group 2 influenza A HAs and also influenza B viruses. These findings will be translated into animal models of influenza and supported by reagents from our highly sophisticated mAb Core. Given our accomplishments in the previous funding period and the combined expertise of the collaborating investigators, we strongly believe that our continued efforts will advance the generation of broadly-protective vaccines which are truly universal in providing protection against group 1, group 2 and influenza B viruses.